Anticipatory activation of the unfolded protein response by epidermal growth factor is required for immediate early gene expression and cell proliferation

作者：Yu Liqun; Andruska Neal; Zheng Xiaobin; Shapiro David J

来源：Molecular and Cellular Endocrinology, 2016, 422(C): 31-41.

DOI：10.1016/j.mce.2015.11.005

• Epidermal growth factor (EGF)
• Breast cancer
• Unfolded protein response (UPR)
• Calcium
• Gene regulation

The onco-protein epidermal growth factor (EGF) initiates a cascade that includes activation of the ERK and ART signaling pathways and alters gene expression. We describe a new action of EGF-EGF receptor (EGFR), rapid anticipatory activation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR). Within 2 min, EGF elicits EGFR dependent activation of phospholipase C gamma (PLC gamma), producing inositol triphosphate (IP3), which binds to IP3 receptor (IP3R), opening the endoplasmic reticulum IP3R Ca2+ channels, resulting in increased intracellular Ca2+. This calcium release leads to transient and moderate activation of the IREl alpha and ATF6 alpha arms of the UPR, resulting in induction of BiP chaperone. Knockdown or inhibition of EGFR, PLC gamma or IP3R blocks the increase in intracellular Ca2+. While blocking the increase in intracellular Ca2+ by locking the IP3R calcium channel with 2-APB had no effect on EGF activation of the ERIC or AKT signaling pathways, it abolished the rapid EGF-mediated induction and repression of gene expression. Knockdown of ATF6 alpha or XBP1, which regulate UPR-induced chaperone production, inhibited EGF stimulated cell proliferation. Supporting biological relevance, increased levels of EGF receptor during tumor progression were correlated with increased expression of the UPR gene signature. Anticipatory activation of the UPR is a new role for EGF. Since UPR activation occurs in <2 min, it is an initial cell response when EGF binds EGFR.

• 出版日期2016-2-15